# Investigating the effects of structural variants on 3D genome organization and gene regulation in cancer genomes

> **NIH NIH U01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2023 · $693,955

## Abstract

Abstract
Three-dimensional genome organization has emerged as a critical component for the proper regulation of gene
expression. Recent years have seen a rapid expansion of the understanding of many of the basic features that
define how genomes are organized in space inside of cells, including the identification of features such as A/B
compartments, Topologically Associated Domains, and chromatin loops. Furthermore, there is evidence that
mutations that alter 3D genome organization can contribute to human disease. This is most evident for a class
of mutations known as structural variants, which includes translocations, inversions, tandem duplications, and
deletions. When these mutations disrupt sequence features that are critical for 3D genome structure, such as
the boundaries between Topologically Associating Domains, this can lead to enhancer-promoter rewiring,
changes in gene expression, and phenotypic consequences. Such effects have been observed both in the
context of germline structural variants that contribute to syndromic disorders of development as well as somatic
structural variants that can lead to cancer. While it has become clear that structural variants can alter 3D
genome organization and gene expression, more recent studies that comprehensively examined structural
variants and gene expression indicate their relationship is considerably more complex. Specifically, in only a
minority of instances do structural variants lead to changes in expression of neighboring genes. Therefore, why
structural variants can have dramatic consequences on 3D genome structure and gene expression in some
contexts but not others is currently unclear. This proposal will investigate the relationship between structural
variants, 3D genome organization, and gene expression in cancer genomes with the goal of understanding
where and when structural variants will actually lead to changes in gene expression that may contribute to
oncogenesis. Specific aim 1 will test whether only specific sets genes are sensitive to structural variant induced
changes in enhancer-promoter communication by examining changes in 3D genome structure and gene
expression in haplotype resolved human tumor samples. Specific aim 2 will use CRISPR/Cas9 genome
engineering to evaluate the effects of structural variant partner regions on induction of oncogene expression.
Specific aim 3 will assess the role of intra-tumor heterogeneity on the effects of structural variants on 3D
genome structure by using novel multi-omic methods for profiling DNA methylation and 3D genome structure
simultaneously within single cells derived from patient tumor samples. Successful completion of these aims will
result in a deeper understanding of the relationship between structural variation, 3D genome organization, and
gene regulation in the context of cancer genomes. In the long term, this will facilitate the use of information
derived from structural variants and 3D genome structure on determining patient pro...

## Key facts

- **NIH application ID:** 10691262
- **Project number:** 5U01CA260700-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Jesse R Dixon
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $693,955
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691262

## Citation

> US National Institutes of Health, RePORTER application 10691262, Investigating the effects of structural variants on 3D genome organization and gene regulation in cancer genomes (5U01CA260700-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10691262. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*